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A Phosphotyrosyl Peptide That Blocks Dimerization of the Human Estrogen Receptor (Estradiol/MCF-7 Cells/Tyrosine Phosphorylation/Dimerization/DNA Binding) STEVEN F

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A Phosphotyrosyl Peptide That Blocks Dimerization of the Human Estrogen Receptor (Estradiol/MCF-7 Cells/Tyrosine Phosphorylation/Dimerization/DNA Binding) STEVEN F Proc. Natl. Acad. Sci. USA Vol. 92, pp. 7475-7479, August 1995 Biochemistry An antiestrogen: A phosphotyrosyl peptide that blocks dimerization of the human estrogen receptor (estradiol/MCF-7 cells/tyrosine phosphorylation/dimerization/DNA binding) STEVEN F. ARNOLD AND ANGELO C. NOTIDES* Departments of Environmental Medicine and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 Communicated by Jack Gorski, University of Wisconsin, Madison, WI, April 28, 1995 (received for review January 13, 1995) ABSTRACT We have previously identified tyrosine-537 scription (STAT) bind DNA as dimers through a reciprocal as a constitutively phosphorylated site on the human estrogen association of a phosphotyrosine on one monomer with a Src receptor (hER). A 12-amino acid phosphotyrosyl peptide homology 2 domain (SH2 domain) on the complementary containing a selected sequence surrounding tyrosine-537 was monomer (15, 16). used to investigate the function of phosphotyrosine-537. The Deletion and mutational analyses have provided evidence phosphotyrosyl peptide completely blocked the binding of the that the C terminus of the steroid hormone receptors is hER to an estrogen response element (ERE) in a gel mobility necessary for receptor dimerization (4). The dimerization of shift assay. Neither the nonphosphorylated tyrosyl peptide the nuclear hormone receptors is reported to be regulated by nor an unrelated phosphotyrosyl peptide previously shown to hydrophobic heptad repeats in the C terminus (17, 18). A inhibit the signal transducers and activators of transcription 22-amino acid sequence from positions 501 to 522 in the C factor (STAT) blocked binding of the hER to the ERE. The terminus of the mouse estrogen receptor was isolated that hER phosphotyrosyl peptide was shown by molecular sizing conferred DNA binding to DNA-binding-deficient mutants chromatography to dissociate the hER dimer into monomers. lacking most of the hormone binding domain (19). Therefore, The hER specifically bound the 32P-labeled phosphotyrosyl it was suggested that this sequence is responsible for the peptide, indicating that the inhibition of ERE binding was dimerization of the estrogen receptor. As of yet no direct caused by the phosphotyrosyl peptide binding directly to the hER evidence has been presented-e.g., glycerol gradient or mo- and blocking dimerization. These data suggest that the phos- lecular sizing chromatography-that this sequence directly phorylation oftyrosine-537 is a necessary step for the formation mediates dimerization. of the hER dimer. In addition, we propose that the dimerization Recently, tyrosine-537 was identified as a phosphorylation of the hER occurs by a previously unrecognized Src homology 2 site on the hER from MCF-7 breast carcinoma cells and the domain (SH2)-like phosphotyrosyl coupling mechanism. Con- hER expressed in Sf9 insect cells. Furthermore, the tyrosine sequently, the phosphotyrosyl peptide represents a class of kinase p6Oc-src was shown to phosphorylate the hER on antagonists that inhibits estrogen action by a mechanism other tyrosine-537 independently of estradiol binding (20). In con- than interacting with the receptor's hormone binding site. trast, previous reports have supported the idea that tyrosine phosphorylation regulates the ability of the receptor to bind The human estrogen receptor (hER) is a member of a large estradiol by an estradiol-dependent tyrosine kinase (21). We family of transcription factors that are regulated by binding sought to investigate the function of the phosphorylation of lipophilic hormones (1). Estrogen responsive elements tyrosine-537 on receptor dimerization and have used a 12- (EREs), which specifically bind the hER, are usually located amino acid phosphotyrosyl peptide corresponding to the se- on the 5' end of estrogen-responsive genes (2). It has been quence surrounding tyrosine-537 of the hER. We demonstrate demonstrated by DNA isocratic chromatography (3), gel mo- a specific phosphotyrosyl peptide-hER interaction that inhib- bility shift analysis (4), molecular weight analyses (5), and its receptor dimerization and suggests the presence of a DNA-receptor immunoprecipitation (6) that the estrogen previously unrecognized mechanism of hER dimerization. receptor binds DNA as a homo- or heterodimer. Therefore, the control of the receptor's capacity to dimerize is central to the receptor's ability to regulate transcription. MATERIALS AND METHODS Several factors such as ligand binding, protein-protein in- Materials. The [,y-32P]ATP (3000 Ci/mmol; 1 Ci = 37 GBq) teractions, and phosphorylation have been shown to modulate and 173-[6,7-3H(N)]estradiol (45.6 mCi/mmol) were pur- the dimerization of transcription factors, including the steroid chased from DuPont/New England Nuclear. Leupeptin, pep- hormone receptors. Estradiol binding promotes the formation statin, and chymostatin were obtained from Peninsula Labo- of the 5S receptor dimer that preferentially binds DNA (3, 5, anti- 7). The dimerization of transcription factors occurs by a ratories. The 4G10 anti-phosphotyrosine monoclonal number of different protein-protein interactive mechanisms. body, p6Oc-src, and Jak2 tyrosine kinase were from Upstate For example, dimerization is promoted by the presence of the Biotechnology (Lake Placid, NY). leucine-zipper (8) or the helix-loop-helix (9) motif in tran- Molecular Sizing Chromatography. The hER from whole scription factors or by accessory proteins, such as the high cell extracts of MCF-7 or Autographa californica nuclear mobility group proteins or the DCoH proteins, which interact polyhedrosis virus (AcNPV)-hER-infected Sf9 cells was puri- with the activating transcription factor 2 (10) or the hepatocyte fied to >90% purity with a 20% yield as described (22, 23). A nuclear receptor la (11), respectively. Posttranslational mod- 2 x 40 cm column of Sephacryl S-300 superfine (Pharmacia) ifications of proteins, principally, serine (12) and tyrosine (13, was equilibrated with buffer at a flow rate of 1 ml/min and 14) phosphorylation, have been implicated in the regulation of dimerization. The signal transducers and activators of tran- Abbreviations: ERE, estrogen response element; hER, human estro- gen receptor; PVDF, poly(vinylidene difluoride); SH2, Src homology 2 domain; STAT, signal transducers and activators of transcription; The publication costs of this article were defrayed in part by page charge BSA, bovine serum albumin; AcNPV, Autographa californica nuclear payment. This article must therefore be hereby marked "advertisement" in polyhedrosis virus. accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 7475 Downloaded by guest on October 1, 2021 7476 Biochemistry: Arnold and Notides Proc. Natl. Acad. Sci. USA 92 (1995) calibrated by using ovalbumin, bovine serum albumin (BSA), kDa ,y-globulin, and Blue dextran at 4°C. The void volume was 45 2 0 6 ml. The purified hER was added to 20 mM Tris HCl, pH 7.4/1 mM EDTA/1 mM EGTA/BSA (1 mg/ml)/15% (wt/vol) glycerol/100 nM [3H]estradiol/protease inhibitors [0.2 mM phenylmethylsulfonyl fluoride/0.5 mM leupeptin/pepstatin (1 mg/ml)/chymostatin (1 mg/ml)] for 1 h at 4°C. The unbound h ER -lo '.4 ~ una [3H]estradiol was removed by absorption to 0.1% dextran- .. .......~~~~~~~~~~~~~~~~~~~~~~~............. coated charcoal for 5 min at 4°C then the [3H]estradiol-hER 4 4 complex was loaded onto the column. 2i 8*....... Peptide Synthesis. All peptides were synthesized by Genosys (The Woodlands, TX), characterized by HPLC and mass spectral analysis, and found to be >90% pure. The phosphor- tz ylated peptide, termed Yp537, which contains the sequence CNVVPLYpDLLLE, and its nonphosphorylated analog Y537 1 2 3 4 correspond to the hER phosphorylation site at tyrosine-537. FIG. 1. Purification of the hER. The hER from MCF-7 and Sf9 The STAT-Yp peptide contains the sequence GYpIKTE (13). cells was purified by ammonium sulfate precipitation and ERE affinity Gel Mobility Shift Assay. A double-stranded 27-bp probe chromatography. The purified hER was then subjected to SDS gel (5'-GATCCTAGAGGTCACAGTGACCTACGA-3') encod- electrophoresis and electrotransferred to a PVDF membrane. The ing theXenopus vitellogenin ERE purified hER (0.25 ,ug) from MCF-7 cells (lane 1) and the hER (1 ,ug) A2 (24) was 32P-end-labeled from Sf9 cells (lane 2) were stainedwith Comassie blue. The hER (0.25 with polynucleotide kinase (25). Gel mobility shift assays for ,ug) from MCF-7 cells (lane 3) or the recombinant hER (1 ;ug) from the hER were performed as described (25). The hER in 20 mM Sf9 cells (lane 4) was reacted with anti-phosphotyrosine monoclonal Hepes, pH 7.5/1 mM EDTA/100 mM KCI/BSA (1 mg/ml)/ antibody 4G10. The hER from the MCF-7 cells reacted more strongly 100 nM estradiol/15% glycerol/protease inhibitors was incu- with the anti-phosphotyrosine antibody than did the hER from the Sf9 bated with 500 ng of poly(dI-dC) for 15 min at 4°C and then cells because it was either phosphorylated more efficiently or dephos- 20 fmol of the 32P-labeled ERE probe was added for 15 min phorylated less during purification (23). at 4°C in a total volume of 20 ,ul. For the STAT gel mobility shift assay, the serum-induced element m67 probe and STAT1 at 5 ,uM and complete at 50 ,uM phosphotyrosyl peptide from epidermal growth factor-treated A431 cells were used as Yp537. In contrast, 500 ,LM nonphosphorylated peptide Y537 described (26). Samples were loaded onto a pre-electrophor- did not inhibit the formation of the hER-ERE complex. The esed 5% polyacrylamide gel followed by electrophoresis with phosphotyrosyl peptide at 500 puM did not interfere with the cooling at 175 V for 3 h in 25 mM Tris, pH 8.0/152 mM formation of the human glucocorticoid receptor-glucocorti- glycine/1 mM EDTA. The gel was dried and autoradiographed coid response element complex, indicating that the inhibition at -70°C. of hER-ERE binding by the phosphotyrosyl peptide was Far Western Blot Analysis.
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